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The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling
Noula Shembade1, Kislay Parvatiyar, Nicole S Harhaj
1Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL 33136, USA.
Abstract:
The RING domain protein RNF11 is overexpressed in breast cancers and promotes tumour growth factor-beta (TGF-beta) signalling. RNF11 has been proposed to regulate TGF-beta signalling by interacting with HECT- and SCF-type E3 ligases; however, the role of RNF11 in other signalling pathways is poorly understood. Here, we demonstrate a novel function of RNF11 as a negative regulator of NF-kappaB and jun N-terminal kinase (JNK) signalling pathways. Knockdown of RNF11 with siRNA resulted in persistent tumour necrosis factor (TNF)- and lipopolysaccharide (LPS)-mediated NF-kappaB and JNK signalling. RNF11 interacted with the NF-kappaB inhibitor A20 and its regulatory protein TAX1BP1 in a stimulus-dependent manner. RNF11 negatively regulated RIP1 and TRAF6 ubiquitination upon stimulation with TNF and LPS, respectively. Furthermore, RNF11 was required for A20 to interact with and inactivate RIP1 to inhibit TNF-mediated NF-kappaB activation. Our studies reveal that RNF11, together with TAX1BP1 and Itch, is an essential component of an A20 ubiquitin-editing protein complex that ensures transient activation of inflammatory signalling pathways.
Insights
RNF11 negatively regulates inflammatory NF-kappaB and JNK signaling pathways. This RING domain protein is crucial for the A20 ubiquitin-editing complex, ensuring transient inflammatory responses.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Cancer Research
Background:
- RNF11 (RING finger protein 11) is overexpressed in breast cancer and influences TGF-beta signaling.
- Its role in other signaling pathways, particularly inflammatory responses, remains largely unexplored.
Purpose of the Study:
- To elucidate the novel function of RNF11 in regulating NF-kappaB and JNK signaling pathways.
- To investigate the molecular mechanisms by which RNF11 modulates these inflammatory pathways.
Main Methods:
- Small interfering RNA (siRNA) for RNF11 knockdown.
- Stimulation with tumor necrosis factor (TNF) and lipopolysaccharide (LPS).
- Analysis of protein ubiquitination and protein-protein interactions.
Main Results:
- RNF11 knockdown led to sustained TNF- and LPS-induced NF-kappaB and JNK signaling.
- RNF11 interacts with A20 and TAX1BP1, negatively regulating RIP1 and TRAF6 ubiquitination.
- RNF11 is essential for A20-mediated inhibition of TNF-induced NF-kappaB activation.
Conclusions:
- RNF11 acts as a negative regulator of NF-kappaB and JNK signaling.
- RNF11 is a key component of the A20 ubiquitin-editing complex, ensuring transient inflammatory pathway activation.
